Historically, natural products or their close analogues have been considered end points in the drug discovery process. To date, this thinking has been quite fruitful. For example, 47% of anticancer drugs and 60% of antibacterial drugs are natural products or very close derivatives. The features that make natural products different from most synthetic compounds (e.g., high Fsp3, low ClogP, presence of stereogenic centers) give these compounds a propensity to bind to their macromolecular target with high affinity and specificity, while retaining the solubility and cell permeability needed for a therapeutic agent. Thus, drug candidates with natural product-like properties may have higher likelihoods of becoming clinical drugs than less structurally complex synthetic compounds. Accordingly, there is a pressing need in the art for new methods to create compounds that are structurally complex and diverse, and for new methods to systematically diversify the structural complexity of natural products.
High-throughput screening is the dominant method to identify lead compounds in drug discovery. As such, the makeup of screening libraries will largely dictate the biological targets that can be modulated and the therapeutics that can be developed. Most compound screening collections consist principally of planar molecules with little structural or stereochemical complexity. While such relatively simple structures are effective in certain settings (e.g., kinase inhibition), they do not offer the arrangement of chemical functionality necessary for modulation of many drug targets. Furthermore, certain chemical properties, such as molecular complexity and multiple stereogenic centers are extremely difficult to build in when producing large collections of compounds for high-throughput screening.
Thus, what is needed in the art is a novel strategy for the creation of small molecules with high structural and stereochemical complexity. Also needed are compounds that are significantly more complex and diverse than those in standard screening collections. New methods to rapidly convert readily available natural products to structurally complex compounds with diverse molecular architectures would provide stereochemically complex molecules that could provide much needed lead compounds for drug discovery.